title: Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.
abstract: Amyloid-β (Aβ), major constituent of senile plaques in Alzheimer's disease (AD), is generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Several lipids, especially cholesterol, are associated with AD. Phytosterols are naturally occurring cholesterol plant equivalents, recently been shown to cross the blood-brain-barrier accumulating in brain. Here, we investigated the effect of the most nutritional prevalent phytosterols and cholesterol on APP processing. In general, phytosterols are less amyloidogenic than cholesterol. However, only one phytosterol, stigmasterol, reduced Aβ generation by (1) directly decreasing β-secretase activity, (2) reducing expression of all γ-secretase components, (3) reducing cholesterol and presenilin distribution in lipid rafts implicated in amyloidogenic APP cleavage, and by (4) decreasing BACE1 internalization to endosomal compartments, involved in APP β-secretase cleavage. Mice fed with stigmasterol-enriched diets confirmed protective effects in vivo, suggesting that dietary intake of phytosterol blends mainly containing stigmasterol might be beneficial in preventing AD.
authors.affiliation: Experimental Neurology, Deutsches Institut für DemenzPrävention (DIDP), and Neurodegeneration and Neurobiology, Saarland University, and Clinic for Internal Medicine III, Cardiology, Angiology and Intensive-Care Medicine, Saarland University Hospital, 66421 Homburg/Saar, Germany, Nutricia Advanced Medical Nutrition, Danone Research, Centre of Specialised Nutrition, 6700 CA Wageningen, Netherlands, Department of Neuroscience and Neurology, University of Kuopio, 70211 Kuopio, Finland, and Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Verena K
authors.initials: VK
authors.lastname: Burg
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Tatjana L
authors.initials: TL
authors.lastname: Rothhaar
authors.forename: Sven
authors.initials: S
authors.lastname: Grösgen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hundsdörfer
authors.forename: Viola J
authors.initials: VJ
authors.lastname: Haupenthal
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Zimmer
authors.forename: Janine
authors.initials: J
authors.lastname: Mett
authors.forename: Oliver
authors.initials: O
authors.lastname: Weingärtner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Laus M
authors.initials: LM
authors.lastname: Broersen
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Tim
authors.initials: T
authors.lastname: Vanmierlo
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005410:Flame Ionization; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010840:Phytosterols / Q000378:metabolism / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013265:Stigmasterol / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D010840:Phytosterols; D002784:Cholesterol; D013265:Stigmasterol